The present invention relates to an agent for improving learning and/or memory comprising as an effective ingredient a quinolinoisoquinoline derivative or a pharmaceutically acceptable acid addition salt thereof.
Learning means to acquire change in behavior, which continues for a relatively long time, which is caused by experience or practice, or the process for acquiring the change in behavior. Memory means to retain information for a certain time, which information is obtained through experience, and to retrieve the information as required. However, the definitions of these two concepts are not simple, and are not independent for each other but most of them overlap. Therefore, learning ability and mneme are often measured by similar experiments in the field of behavioral pharmacology.
Learning includes the steps of encoding, storage, recognition and retrieval. Even if one of these steps is inhibited, disorder of memory occurs (Seiden, L. S. and Dykstra, L. A., Psychopharmacology, a biochemical and behavioral approach. Van Nostrand Reinhold Co., New York(1077)). A representative disease accompanying memory disorder and/or learning disability is dementia. The term xe2x80x9cdementiaxe2x80x9d means the continuous state in which the intellectual ability is reduced, which intellectual ability had ever developed to the normal level. Symptoms of dementia include, in addition to memory disorder and/or learning disability, mood disorder, emotional disorder, intellectual disturbance and psychomotor disturbance. Improvement of memory disorder which likely to cause serious problems in social life is an indispensable action of anti-dementia drugs.
In the brains of patients suffering from senile dementia or Alzheimer""s disease, remarkable reduction in neurotransmitters and biosynthesis enzymes thereof is observed. Therefore, therapy by drugs such as dopamine, noradrenalin, serotonin, acetylcholine and GABA, which act on the transmission process through neurotransmitters is drawing attention. Since it is known that the hypofunction of acetylcholine system is prominent in brains of patients suffering from dementia, the current mainstream of development of therapeutic method for dementia is the development of drugs targeting the activation of acetylcholine nervous system. An anti-dementia drug, tacrine, which has obtained approval, is an acetylcholinesterase inhibitor, and it has been confirmed that improvement of intellectual function to a certain degree is observed in about half of the cases in which the drug is administered. However, this drug has a problem in the hepatic toxicity and choline-related side effects. With Aricept effective for Alzheimer""s disease through the similar mechanism, improvement is observed in about half cases for patients suffering from the dementia in light to medium degree.
On the other hand, references disclosing quinolinoisoquinoline derivatives include Japanese Laid-open Patent Application (Kokai) No. 4-275288, WO93/01186 and WO99/02157. These patent literatures disclose the uses of the derivatives as immunosuppressive agents, analgesics and antitussives. However, these references are totally silent about improvement of learning or memory.
The present inventors intensively studied to discover that specific isoquinoline derivatives exhibit excellent effect for improving learning and/or memory, thereby completing the present invention.
That is, the present invention provides an agent for improving learning and/or memory comprising as an effective ingredient an isoquinoline derivative of the Formula (I): 
{wherein R1 represents hydrogen, C1-C5 alkyl, C4-C7 cycloalkylalkyl, C5-C7 cycloalkenylalkyl, C7-C14 aralkyl, C4-C5 transalkenyl, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, C1-C5 alkanoyl, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or C8-C14 arylalkanoyl; R2 represents hydrogen or OR6 (wherein R6 represents hydrogen, C1-C5 alkyl or C1-C5 alkanoyl); R3 and R3xe2x80x2 independently represent C1-C5 alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonylamino, C1-C5 alkoxy, nitro, amino, or C1-C3 alkylamino; R4 represents hydrogen, hydroxy, C1-C3 alkoxy, benzyl, or C1-C5 alkanoyl or halogen; X represents nitrogen or carbon; R5 exists only when X is carbon, and represents C1-C5 alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonylamino, C1-C5 alkoxy, nitro, amino or C1-C3 alkylamino}
or a pharmaceutically acceptable salt thereof. The present invention also provides a use of said isoquinoline derivative represented by the above-described Formula (I) or the pharmaceutically acceptable salt thereof for the preparation of an agent for improving learning and/or memory. The present invention further provides a method for improving learning and/or memory comprising administering an effective amount of the isoquinoline derivative represented by the above-described Formula (I) or the pharmaceutically acceptable salt thereof.
By the present invention, an agent for improving learning and/or memory was provided, which is useful for therapy of dementia accompanying memory disorder due to a cerebrovascular disease, neurodegenerative disease such as Alzheimer""s disease, endocrine disease, nutritional or metabolic disorder, infectious disease, drug addiction or the like.